Chromanes and process for their production



Patented Apr. 4, 1944 v UNITED STATES PATIENTQ'OFF'ICE CHROMANES AND PROCESS FOR THEIR PRODUCTION Walter John, Gottingen, and Philipp Giinther, Kassel, Germanyassignors to Merck & 00., Inc., Railway, N. J a corporation of New Jersey No Drawing. Application June 25, 1941, Serial No. 399,678. In Germany December 6, 1938 6 Claims. (01. zoo-sea) y This invention relates to new chemical comof methyl magnesium halide and the Grignard positions and compounds and to methods of pro compound from a higher halogenated hydrocarducing the same. bon.

More particularly, it relates to the production According to another modification of our inof substituted chromanes having the biological activity of tocopherols, i. e., Vitamin E, intervention, ketones having the'formula mediates for the production of such chromanes, 111 i R 011, and to methods for producing such compounds. RO/\/ The compounds obtained by the process of the J a present invention have the general formula R I R CH2 R 0R HO v v J (3H2 where R may represent a methyl radical, or two C-KW 'Rs may represent methyl groups, and the re- R maining B. may be a hydrogen atom, and R is a hydrocarbon radical, may be treated'with an Whe e B ay be a methyl p. or two of the organomagnesium halide, whereby atertiary alradicals R may be methyl groups, and t e recohol is formed, which either spontaneously or maining B. may represent hydrogen, and KW is through the action of dehydrating agents, is conany monovalent hydrocarbon radical. verted to the desired chromane.

The syntheses now known for the production of In the first case, for example, 3,4-dihydro-5,7,8- compounds of the Formula I involve the contrilfnethyL3-hydroxycoumarin (Smith et al.,Jourdensation of dior trimethylhydroquinone with nal AmericanChemical Society, vol. 48, page 1693, phytol or its derivatives, u h as p ytyl bromide et seq., 192.6; vol. 58, page 306, et seq., 1936) may or p y n W e ph ol, or i r va iv be employed. This saturated lactone may be rei empl yed in the reaction according to the acted with a mixture of methyl-magnesium halknown syntheses, products of Formula I are obide, and another alkyl magnesium halide to protained, where KW is t 'i e y de duce a chromane substituted in the 2-position tension of these known syntheses to the produc with two alkyl radicals which may be the same or tion of other compound f he n l F r different alkyl radicals. The chromane is prefer- I where KW is a radical other than trimethylably separated out from the mixture of-the reactridecyl, is not practically feasible, because only tion products in the form of an allophanate.

a very limited number of a,fi-unsaturated alco- In-the second case, for example, lA-dimethoxyhols, similar to phytol, are available. 2,5,6-trimethyl-3-(gamma-keto n butyD-ben- It is known that a number of compounds which 5 Zene may be reacted with an organomagnesium differ in constitution from ctoc0phero1 exhibit halide, whereby the ether groups are split up and the biological action of vitamin E, and it is therethe keto group is converted into atertiary alcohol fore desirable to have available practical synthegroup. Thi tertiary alcohol usually is converted $85 for compounds having the eral o u a spontaneously into the corresponding chrom-ane.

but wherein KW is an optional radical- Sueh 40 The processes of our invention are illustrated compounds may be produced accord n to e by the following specific examples, but it will be processes described herein. apparent to those skilled in'the art that many As starting materialsaccording to our invention modifications may be made therein as to the may be emp oye a dihydrocollmalin having the starting materials, etc., without departing from formula, the spirit and scope of the invention and claims. H R om Example I HO/\/ Grignard solutions .from 0.486- gm. of magnet slum and 5.0 gms. ofldodecyl' bromide in 15 cc, of R/\ 5o ether, and from 0.365 gm. of magnesium and 2.16

gms. of methyl iodide in 10 00', of ether are prewhere R may represent a methyl group, or two pared. The two solutions arecQm-bined, diluted Rs may represent methyl groups, th remaining with 10 cc. of benzene and 10 cc; of anisole, and Rrepresenting hydrogen. the mixture is allowed to run during the course The dihydrocoumarin is reacted withamixture of several minuteawith vigorous stirring and while bubbling through nitrogen, into a solution of 1.03 gms. of dihydrocoumarin in 30 cc. of benzene and cc. of anisole, heated to about 410 C. A voluminous precipitate is developed. The mixture is heated to the boiling point, whereby the precipitate decreases in volume. The main portion of the ether is then filtered off by applying a mild vacuum, and the boiling is continued for three hours under refluxing, whereby the precipitate is dissolved almost completely. Then while avoiding the entrance of air, all solvents are evaporated under vacuum. The remaining lightgray residue is treated in a vessel with continuuous outside water cooling with a cooled mixture of cc. of ethanol and 20 cc. of concentratedhydrochloric acid, whereby it is gradually dissolved with slight warming. When solution is complete, it is boiled under refluxing for one quarter hour, while bubbling hydrochloric acid gas through simultaneously; during this procedure the solution must remain almost completely homogeneous, without appreciable quantities of oil separating. On boiling, the solution turns a faintly yellowish brown. color; if the reaction product has repeatedlycome into contact with air, the color will be dark brown. The product is taken up in benzene, the aqueous portions are washed again with benzene, the combined benzene solutions are washed with water and bicarbonate solution and are dried with sodium sulfate. The thus obtained benzene solution is made up to a volume of 00., passed through an aluminum oxide column about 15 cm. high and with a diameter of 3 cm., and washed with benzene. The following fractions are obtained;

colored very slightly and contains a mixture of chromanes. (4) The fraction retained in the chromatogram contains only very little chromane mixture.

The substance contained in fraction 2 is dissolved in alcohol, any hydrocarbon 0241-150 still present remains behind and is filtered off. When well cooled, some semi-solid material which separate first, melts at room temperature, and may be identified as didodecyl-trimethyl-hydroxychromane. After prolonged standing, dodecyltetramethyl-hydroxy-chromane separates out in theform ofbunches of fine feathery crystals. It is recrystallized from alcohol and finally melts at -61 C. Altogether, chiefly from fraction 2, to a lesser extent from fraction 3, 200-250 mg. dodecyl-tetramethyl-hydroxy-chromane are obtained. The ultra-violet absorption spectrum of the chromane with a melting point of 61 C. corresponds to that of a-tocopherol, and its behavior towards silver nitrate is similar.

The allophanate of dodecyl-tetramethyl-hydroxy-chromane melts at 180 0.; it crystallizes from methanol in the form of fine needles,

Example II 1A gins. of p-dimethoxy-trimethyl-benzaldehyde (Smith, Journal American Chemical 800., vol. 56, page 472, et seq., 1934) is dissolved in 10 cc. of acetone, treated with 1 cc. of 1 N sodium hydroxide and mechanically shaken at room temperature. After about 10 minutes the solution becomes turbid and a faintly yellowish product separates out. After shaking for about three hours, the precipitate is filtered 01f; it melts at 188 C. after recrystallization from acetone. According to its analytical composition, this prodnot is a dibenzylidene derivative. The filtrate is neutralized with H2SO4 and is then extracted with ether. The material obtained from the ether extraction is crystallized from petroleum ether fwith strong cooling (freezing mixture). It ocours in the form of faintly yellowish crystals having a melting point of about 61-62" C. The yield of benzylidene acetone derivative is to the yield of dibenzylidene acetone derivative is 10-15%.

500 mg. of the compound with a melting point of 62 C. is hydrogenated in 30 cc. of pure alcohol in the presence of about 500 mg. palladium black, until all of the hydrogen is taken up (about one hour). The solution is diluted with water, the hydrogenation product is extracted with ether and is recrystallized from aqueous methanol. 1,4-dimethoxy- 2,5,6-trimethyl-3- (gamma-keto -nbutyD-benzene is obtained in the form of fine soft needles having a melting point of 76 C. in better than y 600 mg. of the hydrogenation product with a melting point of 76 C. is dissolved in 5 cc. of absolute ether and is added drop by drop to a Grignard solution prepared from 400 mg. of methyl iodide and 80 mg. of magnesium in 5 cc. of ether, and boiled under refluxing for about three hours. It is then decomposed in the usual manner with ice and hydrochloric acid, extracted with ether, and then the concentrated residue from the ether extraction is boiled under refluxing for about three hours with 10 cc. of glacial acetic acid and 3 cc. of hydrobromic acid (density=l.49). After cooling, it is treated with water, extracted with ether, the ether is washed and dried. The colorless residue remaining after evaporation of the ether crystallizes spontaneously. From petroleum ether, well-defined crystals having a melting point of about 93 C. are obtained, which by their mixed melting point and their ultraviolet absorption are found to be identical with 2,2,5}?,8-pentamethyl-6-hydroxychromane.

By proper modification of the organomagnesium halide used in treatment of the hydrogenation product as in Example II, other chromanes of Formula I, in which KW is a monovalent higher hydrocarbon radical, may be prepared. Thus, for instance, if dodecyl magnesium bromide is substituted for the methylmagnesium iodide specifically exemplified in Example 11, 2,5,7,8-tetramethyl-2-N-dodecyl-6-hydroxy chromane is obtained as end product. The esters, as for instance the allophanate, of this chromane are prepared as described in Example I.

Thi application is a continuation-in-part of our co-pending application Serial No. 306,120, filed November 25, 1939, Patent 2,245,147.

We claim:

1. The process for the production of compounds of the general formula where R is selected from the group consisting of hydrogen and methyl, and KW is any monovalent hydrocarbon radical, which comprises reacting a ketone of the formula where R is selected from the group consisting of hydrogen and methyl, and R. is a hydrocarbon radical, with an organomagnesium halide.

2. The process for the production of compounds of the general formula where R is selected from the group consisting of hydrogen and methyl, and KW is a dodecyl radical, which comprises reacting a ketone of the formula where R is selected from the group consisting of hydrogen and methyl, and R is a hydrocarbon radical, with dodecyl magnesium bromide.

5. The process for the production of 2,2,53,8- pentamethyl-B-hydroxy chromane which comprises reacting l,4-dimethoxy2,5,fi-trimethyl-3- (gamma-keto-n-butyl)-benzene with methyl magnesium halide.

6. The process for the production of compounds of the general formula where R is selected from the group consisting of hydrogen and methyl, which comprises reacting a ketone of the formula R 9 a I OH:

R O-GH:

where R is selected from the group consisting of hydrogen and methyl, and R is a hydrocarbon radical, with methyl magnesium halide.

WALTER JQHN. PHILIPP GUN'IHER.

CERTIFICATE OF CORRECTION. Patent No. 235,605. April i 19%.

WALTER JOHN, ET AL.

It is hereby certifiedlthat error appears in the printed specification of the above numbered patent requiring correction as follows: Page 2, first column, line 555). for "separate" read -separates; page 5, second column, line 5 claim 6, in the formula, for '"oR" read --OR'-; and that the said Letters Patent should be read with this correction therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 50th day of May, A. D. 19th.

Leslie Frazer (Seal) Acting Commissioner of Patents. 

